5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK1 receptor antagonists: Structural modifications at the tryptophan domain

Citation
Jm. Bartolome-nebreda et al., 5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK1 receptor antagonists: Structural modifications at the tryptophan domain, J MED CHEM, 42(22), 1999, pp. 4659-4668
Citations number
44
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
42
Issue
22
Year of publication
1999
Pages
4659 - 4668
Database
ISI
SICI code
0022-2623(19991104)42:22<4659:5PA>2.0.ZU;2-B
Abstract
Analogues of the previously reported potent and highly selective CCK1 recep tor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhyro pyrido-[1,2-c]pyrimidine (2a) were prepared to explore the structural requi rements at the Boc-tryptophan domain for CCK1 receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedo m, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highly strict structur al requirements: the type and orientation of the Trp side chain, the H-bond ing acceptor carbonyl group of the carboxamide bond, and the presence of th e Trp amino protection Boc. Replacement of this acid-labile group with 3,3- dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to anal ogues 14a and 15a, which retained a high potency and selectivity in binding to CCK1 receptors, as well as an in vivo antagonist activity against the a cute pancreatitis induced by caerulein in rats. Oral administration of comp ounds 14a and 15a also produced a lasting antagonism to the hypomotility in duced by CCK-8 in mice, suggesting a good bioavailability and metabolic sta bility.